小柯机器人

美国约翰霍普金斯大学Kellie N. Smith、Drew M. Pardoll、Srinivasan Yegnasubramanian和Hongkai Ji研究团队合作取得最新进展。他们揭示新抗原特异性肿瘤浸润淋巴细胞 (TIL)在抗 PD-1 治疗的肺癌中的转录程序。该项研究成果发表在2021年7月21日出版的《自然》上。

他们在新辅助抗 PD-1 治疗的非小细胞肺癌 (NSCLC) 中使用特异性 T 细胞测定的突变相关新抗原 (MANA)功能扩增来鉴定 MANA 特异性 T 细胞克隆。他们使用T 细胞受体作为条形码，使用耦合的单细胞 RNA 测序和 T 细胞受体测序来追踪和分析它们在肿瘤微环境中的转录程序。他们在 TIL 中发现 MANA 和病毒特异性克隆，无论反应如何，MANA、流感病毒和 Epstein-Barr 病毒特异性 TIL 都有独特的转录程序。尽管暴露于同源抗原，MANA 特异性 TIL 表达不完全激活的溶细胞程序。MANA 特异性 CD8 T 细胞具有组织驻留记忆 (TRM) 细胞的标志性转录程序，但与流感特异性 TRM 细胞相比，白细胞介素 7 受体 (IL-7R) 水平低且对白细胞介素 7 (IL-7) 的反应较弱。

与来自应答肿瘤的克隆相比，来自非应答肿瘤的 MANA 特异性克隆表达 T 细胞受体，配体依赖性信号显著降低，主要局限于 HOBIThigh TRM 亚群，并协同上调检查点、杀伤抑制受体和 T 细胞活化抑制剂。这些发现为克服对 PD-1 阻断的耐药性提供了重要的见解。

据介绍，PD-1 的阻断可释放 CD8 T 细胞 ，包括那些特异于MANA的细胞，但肿瘤微环境中的因素可以抑制这些 T 细胞反应。单细胞转录组学揭示了TIL中的整体 T 细胞功能障碍程序。然而，大多数 TIL 不识别肿瘤抗原 ，并且对 MANA 特异性 TIL 的转录程序知之甚少。

附：英文原文

Title: Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Author: Justina X. Caushi, Jiajia Zhang, Zhicheng Ji, Ajay Vaghasia, Boyang Zhang, Emily Han-Chung Hsiue, Brian J. Mog, Wenpin Hou, Sune Justesen, Richard Blosser, Ada Tam, Valsamo Anagnostou, Tricia R. Cottrell, Haidan Guo, Hok Yee Chan, Dipika Singh, Sampriti Thapa, Arbor G. Dykema, Poromendro Burman, Begum Choudhury, Luis Aparicio, Laurene S. Cheung, Mara Lanis, Zineb Belcaid, Margueritta El Asmar, Peter B. Illei, Rulin Wang, Jennifer Meyers, Kornel Schuebel, Anuj Gupta, Alyza Skaist, Sarah Wheelan, Jarushka Naidoo, Kristen A. Marrone, Malcolm Brock, Jinny Ha, Errol L. Bush, Bernard J. Park, Matthew Bott, David R. Jones, Joshua E. Reuss, Victor E. Velculescu, Jamie E. Chaft, Kenneth W. Kinzler, Shibin Zhou, Bert Vogelstein, Janis M. Taube, Matthew D. Hellmann, Julie R. Brahmer, Taha Merghoub

Issue&Volume: 2021-07-21

Abstract: PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

DOI: 10.1038/s41586-021-03752-4

Source: https://www.nature.com/articles/s41586-021-03752-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html